Kinetoplastid parasites, such as Trypanosome cruzi (T. cruzi), Trypanosoma brucei (T. brucei), and Leishmania spp., utilize and depend on the pentose phosphate pathway (PPP) for the reducing agent NADPH and also rely on the PPP for support for nucleic acid and nucleotide biosynthesis. The PPP is essential for these organisms and obstruction of the pathway leads to cell death and can be caused by inhibition of the enzyme, glucose 6-phosphate dehydrogenase, for instance by use of a drug. In order to create a therapeutic drug, an inhibitor should selectively block the parasite homologue and avoid cross-reactivity with the human homologue (i.e., bind weaker or not bind at all), giving rise to a good selectively ratio.
T. cruzi is the causative agent for Chagas' disease and benznidazole and nifurtimox are the two main clinically available treatments available in Latin America. These drugs have the potential for resistance because they were developed over 35 years ago and alternative drugs have not emerged. T. brucei is the causative agent for human African sleeping sickness and various drugs are available, such as pentamidine, suramin, eflornithine, and melarsoprol. Leishmania spp. are protozoan parasites causing Leishmaniasis and medical intervention requires treatment such as pentavalent antimony-based medicines, or more expensive treatments such as amphotericin B, miltefosine, or paramomycin. The drugs for these kinetoplasid diseases all require substantial improvements in their tolerability, safety, and efficacy.
A need exists for new drugs that strongly bind to drug targets found in these parasites. Such a need includes inhibitors of the glucose kinase enzymes, hexokinase and glucokinase. A need also exists for such inhibitors that will provide an alternative to the clinically used drugs at the present time.